Maternal smoking during pregnancy is associated with morbidity and mortality in infants and behavioral deficits in infants and older children. Despite pervasive sanctions against smoking during pregnancy, 13-30% of infants are born exposed. Given continued high exposure rates and links to costly offspring outcomes, novel approaches are needed to identify and protect high risk offspring and help pregnant smokers quit. The proposed study offers a paradigm shift in identifying real-time, pre-birth neurobehavioral and neural markers of risk from maternal smoking using 2 and 3-dimensional fetal ultrasound. Specifically, we test the proposal that: a) maternal smoking will influence trajectories of fetal neurobehavior, stress response, and neural and neuroendocrine structures over pregnancy, and b) richly characterized trajectories of fetal neurobehavior, stress response, and neural structures will predict infant neurobehavioral deficits. Using an approach pioneered by our group (2D ultrasound combined with fetal actocardiography), our preliminary work revealed effects of maternal smoking on fetal neurobehavioral deficits and altered stress response during third trimester. However, fetal developmental trajectories leading to third trimester deficits are not known. Further, although structural brain deficits have been proposed as a key candidate mechanism underlying links between maternal smoking and offspring neurobehavioral deficits, no studies have integrated neural and behavioral markers of risk from maternal smoking. The advent of 3D ultrasonography offers higher resolution fetal images, allowing volumetric characterization of specific fetal brain and neuroendocrine structures. Seminal preliminary work from our group demonstrated feasibility of 3D assessment and revealed volume decrements in fronto-cerebellar brain structures in fetuses exposed to maternal smoking. The proposed study is an intensive investigation of ultrasound markers of risk from maternal smoking. Our study involves prospective investigation of smokers and controls over pregnancy. Three fetal ultrasound assessments will be completed using highest safety standards to observe fetal behavior, response to mild stress (vibro-acoustic stimulus), and 3D volumetric assessment of fetal neural (fronto-cerebellar regions) and neuroendocrine (adrenal gland) structures, followed by two infant neurobehavior and cortisol reactivity assessments. Our goals are to determine effects of maternal smoking on: 1) trajectories of fetal neurobehavioral deficits, 2) alterations in fetal stress response, and 3) volume decrements in neural and neuroendocrine structures over pregnancy. We will then test the proposal that trajectories of fetal neuro-behavioral and neural markers of risk predict infant neurobehavioral deficits and stress response. Results offer potential for: a) promoting discovery of mechanisms of maternal smoking in real- time during pregnancy, b) identifying new pre-birth markers of risk that could improve clinical care for pregnant smokers and other high-risk pregnancies, c) identifying novel therapeutic targets to protect exposed fetuses, and d) developing new foci for intervention efforts with pregnant smokers.